Enhancement of fracture repair in rats with streptozotocin-induced diabetes by a single injection of biodegradable microcapsules containing a bone formation stimulant, TAK-778

Abstract

The feasibility of using microcapsules containing a b o n e f o r m a t i o n s t i m u l a n t , ( 2 R , 4 S ) -( − ) -N -( 4diethoxyphosphorylmethylphenyl)-1,2,4,5-tetrahydro-4methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2carboxamide (TAK-778) to enhance fracture repair was assessed in rats with streptozotocin-induced diabetes. The release profile of the microcapsules was designed to mimic a dosing regimen of multiple injections of TAK-778 solution. The solution was injected locally every third day from day 0 (the day of operation) to day 27 according to several dosing regimens, and fracture repair was assessed at day 28. The production of callus was most prominent when TAK-778 solution was injected so that 50-75% of the total dose (5 mg TAK-778/site) was administered during the first half of the treatment period. Thus, injectable microcapsules of 30 m in mean diameter were prepared in order to release TAK-778 over 4 weeks using a biodegradable polymer, poly(d,l-lactic/glycolic) acid, with a copolymer ratio of 85:15 (mol/ mol) and an average molecular weight of 14,000. A single local injection of the microcapsules markedly enhanced fracture repair, which resulted in recovery of destructive bending strength of the bone at day 28. Histologically, the injection of TAK-778 microcapsules stimulated both fibrous and cartilaginous proliferation and periosteal ossification in the callus at day 7; bony bridge formation was observed at day 28. At day 56, the callus was remodeled and cortical bony union was evidenced in the microcapsule-treated fractures compared with the controls, which showed only fibrous union.

Preparation and evaluation of biodegradable microspheres containing a new potent osteogenic compound and new synthetic polymers for sustained release

“…The recovery of microspheres was shown to be 50-70% for all preparations. For the mean particle sizes of the microspheres ( Table 2), all of the microspheres constructed from PLA and PLGA polymers were in the range of approximately 10-50 m, which is considered to be an adequate size (Hoshino et al, 2000). For the microspheres constructed from the PLA-PEG polymers, the mean particle sizes of microspheres constructed from PLAPEG9604H, PLAPEG9604L, PLAPEG8812, and PLAPEG8515H with a PEG proportion of between 4 and 15% were in the range of approximately 30-45 m. However, when the proportion of the PEG component exceeded 20%, it became technically difficult to prepare these microspheres.…”

Diabetic Fracture Healing

“…These studies include the use of lowintensity pulsed ultrasound (US), biodegradable microcapsules containing bone formation stimulant (TAK-778), recombinant human bFGF, local delivery of insulin, and the percutaneous injection of platelet-rich plasma (PRP) [24,[50][51][52][53]. US normalized the diabetes-related impairment in fracture callus strength [52]; however, US did not affect cellular proliferation in the early diabetic fracture callus.…”

“…The effect of US in a diabetic fracture healing model does not appear to be mediated through the normalization of cell number but possibly through increased matrix production. Hoshino and colleagues [53] reported locally delivered microcapsules of TAK-778-enhanced fracture repair in streptozotocin-induced diabetic rats. TAK-778 increased the bending strength of diabetic bone at 4 weeks and 8 weeks.…”

Effect of Microcapsules Containing TAK-778 on Bone Formation Around Osseointegrated Implants: Histomorphometric Analysis in Dogs

“…8 To evaluate the in vivo osteogenic potential of TAK-778, it was developed a sustained release microcapsules consisted of a biodegradable polymer, poly (dl-lactic/glycolic) acid, and TAK-778, which allow the drug release for 4 weeks after the injection. 6 Using this release system, TAK-778 has induced bone regeneration and stimulated fracture healing. 9,10 In addition, TAK-778 enhances new bone formation on hydroxyapatite and bioactive glass ceramics implanted into rabbit tibiae.…”

“…In vitro studies have shown that TAK-778 increases both alkaline phosphatase activity in rat bone marrow cell culture and the action of bone morphogenetic protein in mouse osteoblastic cell line MC3T3-E1. 4 6 Recently, we showed that TAK-778 enhances osteoblast differentiation in human bone marrow cell culture in a dose-dependent way. 7 Also, it was observed that TAK-778 maintains its effect on osteoblast differentiation in the presence of titanium.…”